Collaboration between two GlycoNet researchers has led to the discovery of a novel class of enzymes and an increased understanding of how to potentially fight a common and deadly fungal infection.
Aspergillus fumigatus (AF) is the second-most common fungal infection occurring in hospital. The invasive form of the infection, which occurs in immunocompromised patients, has a mortality rate of more than 50% despite current antifungal treatments. But with their recent findings published in the Journal of Biological Chemistry (JBC), GlycoNet researchers Dr. P. Lynne Howell (The Hospital for Sick Children) and Dr. Don Sheppard (McGill University) are one step closer to developing a treatment for AF.
The paper, titled “Sph3 Is a Glycoside Hydrolase Required for the Biosynthesis of Galactosaminogalactan in Aspergillus fumigatus,” was featured on the cover of the November 13 issue of JBC and was named Paper of the Week.
“Work form our groups has found that a polysaccharide called galactosaminogalactan (GAG) is a really important virulence factor in AF,” explained Natalie Bamford, first author of the paper and a third-year doctoral student in Howell’s lab. “It’s part of the biofilm coat that the fungus makes inside the body and helps protect the organism from the host immune response. My project was to look at the cellular machinery that makes this polysaccharide.”
What Bamford and her colleagues found was that a protein called Sph3 was key in producing GAG, and therefore in producing the protective biofilm around Aspergillus.
They also discovered that Sph3—which was part of the spherulin 4 family, a protein family with no known function—is a novel glycoside hydrolase enzyme and proposed an active site for this new family. This discovery opens the door for new areas of study around this protein.
“By our characterization of this enzyme, where we’ve shown it’s a glycoside hydrolase, all of the sudden you’ve attached a function to any protein that would match with a spherulin 4-like family,” says Howell. “It opens up a whole new avenue of potential areas to research in that class of proteins.”
This study lays the groundwork for additional research being conducted by Howell and Sheppard on treating AF. Sph3 is one of several hydrolases they are studying that can degrade the protective biofilm of the fungus, which has great potential in making existing treatments more effective.
“By using the hydrolases, you essentially chew up the protective matrix around the fungus and therefore reduce the tolerance the fungus has top antifungals, and so the existing treatments become more effective,” explains Howell. “What we are currently trying to do is develop this particular enzyme, as well as other hydrolases, for combination therapies in which you’d use the hydrolase plus an antifungal.”
Howell explains that collaboration with the Sheppard lab was key in this research.
“Partnership in this particular case is important because we have no expertise in fungal genetics,” she said. “Finding these connections to people that have common interest but have complementary expertise allow us to do something greater.”
Support for this project was provided by the Canadian Institutes of Health Research, Cystic Fibrosis Canada, and the Canadian Foundation for Innovation. Salary support has been provided by Fonds de Recherche Quebec Santé, the Canada Research Chairs program, the Natural Sciences and Engineering Research Council of Canada, The Hospital for Sick Children, the University of Toronto, the Ontario Graduate Scholarship Program, the Canadian Institutes of Health Research, and Cystic Fibrosis Canada.
The research utilized the Canadian Light Source (supported by NSERC, CIHR, the National Research Council Canada, the Province of Saskatchewan, Western Economic Diversification Canada, and the University of Saskatchewan) and National Synchrotron Light Source (supported by the United States Department of Energy Office and by the National Center for Research Resources Grant P41RR012408 and the National Institute of General Medical Sciences Grant P41GM103473, from the National Institutes of Health).